Morphinan-6α-ols, including such compounds as dihydrocodeine, oxymorphol, oxycodol and nalbuphine are important morphine derivatives due to their behaviour as potent analgesics or antagonists. Some prior synthetic routes to these compounds include;                from codeine or morphine, where the 6α-stereochemistry of the 6-hydroxy morphinan was already fixed by the stereo-chemistry of the natural product (see for example U.S. Pat. No. 6,887,999 for the hydrogenation of codeine to dihydrocodeine),        Reduction of the 7,8-didehydro derivatives morphinan-6-ones using metal hydride reducing agents (e.g. sodium borohydride, lithium tri-sec-butyl borohydride) followed by hydrogenation to give the pure 6α-isomer of the corresponding morphinan-6-ol. (Sargent et al., “Hydroxylated codeine derivatives”, Journal of Organic Chemistry, 23, 1247-1251, (1958), and A. C. Currie et al., J. Chem. Soc., 1960, 773.) This strategy was also used to convert 14-hydroxynormorphinones preferably to the 6α-epimer of the corresponding 14-hydroxydihydromorphine (preferably N—O3-bis(ethoxycarbonyl)-14-hydroxynormorphinone to N—O3-bis(ethoxycarbonyl)-14-hydroxydihydronormorphine; Kavka, “Preparation of nalbuphine having low levels of β-epimer”, U.S. Pat. No. 5,756,745). Similarly, Cheng et al. converted methoxymethyl-protected naloxone to the corresponding 6-α epimer using potassium and sodium tri-sec-butylborohydride (Na and K-selectride respectively), sodium triethylborohydride and sodium triacetoxyborohydride in high chemical yield and >99% selectivity for the α-epimer (Stereoselective reduction of a morphinone, WO 2007/121114). U.S. Pat. Nos. 5,208,338 and 5,336,483 describe the preparation of radiolabeled N-substituted-6-iodo-3, 14-dihydroxy-4,5-α-epoxymorphinans (Scheme 4) which includes the selective reduction of the 6-carbonyl group using K-selectride, specifically described for the synthesis of 6α-naltrexol from naltrexone. TLC measurements indicated the absence of the epimeric 6β-isomer.        By contrast, reduction of oxymorphone (the morphinan-6-one saturated at the 7,8 position) using sodium borohydride promoted formation of the 6α morphinan-6-ol contaminated with significant amounts of the 6β isomer. (Burke and Rice., “Probes for narcotic receptor mediated phenomena. 11. Synthesis of 17-methyl- and 17-cyclopropylmethyl-3,14-dihydroxy-4,5α-epoxy-6β-fluoromorphinans (FOXY and CYCLOFOXY) as models of opioid ligands suitable for positron emission transaxial tomography.” Heterocycles, 23, 1985, 99-106.)        Similarly, lithium aluminum hydride or sodium borohydride reduction of 8,14-dihydroxydihydrocodeinone(oxycodone) leads to epimeric dihydroxydihydrocodeines(oxycodols) (Sargent et al., “Hydroxylated codeine derivatives”, Journal of Organic Chemistry, 23, 1247-1251, (1958)).        Similarly, reduction of naltrexone with either sodium borohydride in tetrahydrofuran or lithium tri-sec-butylborohydride in tetrahydrofuran at −78° C. gave 6α-naltrexol contaminated with traces of the 6β epimer. (Brine et al., “Ring C conformation of 6β-naltrexol and 6α-naltrexol. Evidence from Proton and Carbon-13 nuclear magnetic resonance.” Journal of Organic Chemistry, 41, (1976) 3445-3448.)        Other literature report the reduction of naltrexone to 6α-naltrexol, e.g. L. D. Olsen et al., J. Med. Chem., 1990, 33, 737-741 or the reduction of 3-O-tert-butyldimethylsilyl protected naltrexone to the corresponding alpha isomer (G. A. Brine et al., J. Org. Chem., 1976, 41(21), 3445-3448) by using L-selectride in THF at −78° C. Traces of the beta isomer formed during the reduction were removed by chromatography or recrystallization.        
The main drawbacks of the aforementioned procedures from the literature are low selectivities of the reductions (formation of 5-10% beta-isomer) resulting in a tedious procedure for the removal of the contaminant. Such removal requires either several recrystallizations giving an unacceptable loss of yield or a purification by column chromatography, which is not a commercially viable procedure. In case of the preparation of 6α-naltrexol from naltrexone, L-selectride was used as reducing agent at very low temperatures of −78° C., or 3-O-tert-butyldimethylsilyl protected naltrexone was used, making the process more complicated and expensive due to the need for special refrigerating equipment and/or expensive protecting groups.
In contrast to the metal hydride reducing agents traditionally used for the reduction of ketones to alcohols, hydrogenation does not require very low temperatures, or prior protection of the 3-hydroxy group, followed by de-protection to the desired 3-hydroxy-6α-morphinol and is operationally simpler and creates little or no waste during the processing. Few examples exist for the hydrogenation of the ketone group of morphinan-6-ones.                Hydrogenation of dihydrohydroxycodeinone (also known as oxycodone) in 10% aqueous acetic acid as solvent and platinum oxide as catalyst gave a mixture of 6α- and 6β-epimers of oxycodol with the 6α-epimer being the major product (Lutz R. E., and Small L., “Reduction studies in the morphine series. X. Hydroxycodeinone.” Journal of Organic Chemistry, 4, 220-233, (1939)). In this solvent mixture the reaction clearly was not stereo-selective.        There is only one example of a hydrogenation of a morphinan-6-one to a morphinan-6-ol. Hydrocodone was hydrogenated in ethanol as solvent using platinum oxide as catalyst (Grew and Powles, “Manufacture of 1-Dihydrocodeine” U.S. Pat. No. 3,830,819). The epimeric purity of the morphin-6-ol product was not mentioned in this example.        
There remains a need for an efficient stereo-selective and environmentally friendly route to the pure 6α-epimer of morphinan-6-ols, particularly 14-hydroxymorphinan-ols. Increasingly, morphinan-6-ones and 14-hydroxymorphinan-6-ones are being used as intermediates in the synthesis of the corresponding morphinan-6-ols because they are available conveniently and in high yield from opiate raw materials thebaine and oripavine, both of which became commercially available in large quantities only relatively recently.